A novel anti-HIV activity of CCR6 via APOBEC3G: relevance to CNS infection Abstract We have shown that when defensin hBD2 and chemokine MIP-31 (CCL20) bind to their cellular receptor, CCR6, they induce an intracellular antiviral activity against HIV that is absent in cells that do not express CCR6. While direct inactivation of enveloped viruses including HIV has been implicated as one mechanism of defensins, to our knowledge, HIV inhibition mediated through CCR6 is novel. The mechanism occurs post entry but at or before reverse transcription, and appears to be due to increased expression of the intracellular antiviral protein APOBEC3G. Inhibition is abrogated by pertussis toxin, suggesting the involvement of G1i-dependent signal transduction. CCR6 is expressed on cells that are highly relevant to HIV infection;they include memory T cells, dendritic cells, activated macrophages, microglia and Th17 cells. Defensins that bind to CCR6 are primarily expressed by epithelial cells and astrocytes, while MIP-31 is produced by mucosal epithelial cells, activated peripheral blood mononuclear cells and astrocytes. Since both CCR6 and its ligands are expressed in the central nervous system in cells highly relevant to HIV infection, an HIV suppressive mechanism that targets CCR6 may play a critical role in controlling HIV infection and CNS symptoms. Further, elucidation of the intracellular pathways and the step(s) in the HIV life-cycle limited by CCR6 activation could provide insights into virus-host interactions early in infection and identify new targets for antiviral therapy. We propose to identify APOBEC3G as the effector molecule of the antiviral activity mediated by CCR6 in primary cells;to demonstrate that CCR6- induced signal transduction increases APOBEC3G expression and identify what is the critical specific pathway;to demonstrate the efficacy of CCR6-mediated HIV inhibition on a broad spectrum of primary and non-B viral isolates;and to measure the expression of CCR6, CCR6 ligands, and APOBEC3G in clinical specimens. PUBLIC HEALTH RELEVANCE: The studies proposed here will investigate the mechanism of inhibition of HIV by a cellular receptor called CCR6. These studies are highly relevant to prevention and treatment of HIV infection because they will contribute knowledge that can be used to develop novel anti-HIV drugs that will target CCR6.